For understanding the invention, firstly the following terminological background is important. The activation of resting T cells for proliferation and functional differentiation firstly requires the occupation of two surface structures, so-called receptors: 1. of the antigen receptor having a different specificity from cell to cell and being necessary for detecting antigens, for instance viral fission products; and 2. of the CD28 molecule equally expressed on all resting T cells with the exception of a sub-group of the CD8 T cells of man, the CD28 molecule naturally binding to ligands on the surface of other cells of the immune system. This is the “costimulation” of the antigen-specific immune reaction by CD28. In a cell culture, these processes can be simulated by occupation of the antigen receptor and of the CD28 molecule with suitable monoclonal antibodies (mAb's). In the classic system of costimulation, neither the occupation of the antigen receptor nor that of the CD28 molecule alone will lead to a T cell proliferation, the occupation of both receptors is however effective. This observation was made in T cells of humans, mouse and rat.
There are however also known CD28-specific mAb's that can initiate the T cell proliferation without costimulation. Such a superagonistic, i.e. independent from the occupation of the antigen receptor, activation of resting T lymphocytes by CD28-specific mAb's is known in the art from the document Tacke et al., Eur. J. Immunol., 1997, 27:239-247. According thereto, two types of CD28-specific monoclonal antibodies having different functional properties are described: costimulatory mAb's costimulating the activation of resting T cells only with simultaneous occupation of the antigen receptor; and superagonistic mAb's, which can activate T lymphocytes of all classes in vitro and in the test animal for proliferation without occupation of the antigen receptor. From the documents DE 197 22 888 and PCT/DE03/00890 are also known CD28-specific mAb's, which efficiently activate T lymphocytes in vitro as well as in vivo without TCR stimulation, i.e. which act “superagonistically”. The mAb's, at least those, which are directed against human CD28, are also called SuperMAb's.
The chronic lymphatic leukemia of the B-cell series (chronic lymphocytic leukemia of the B-cell type, B-CLL) is with an incidence of 3 per 100,000 inhabitants the most frequent leukemia of adults (Landis et al., 1999). The disease is characterized by a progressive accumulation of malignant monoclonal B lymphocytes in the blood, lymph nodes, liver and bone marrow. With progressing disease, the lymphocyte count in the blood will be increased, lymph nodes, liver and spleen will become enlarged, and an anemia and thrombocytopenia will occur (Caligaris-Cappio, 2000; Rozman and Montserrat, 1995). A curative therapy of the B-CLL is not possible at present.
To the main complications of the B-CLL belong infections, for which can be blamed, among other reasons, the T cell defects or low T cell counts to be observed in many patients (Cantwell et al., 1997; Scrivener et al., 2003).
A limited function can further also be found in the tumor cells themselves. The property of the B-CLL B cells, to act as antigen-presenting cells (APC's) and to thus be detected and eliminated by tumor-specific T cells, is substantially limited. The reason for this, among others, is that B-CLL B cells do not express or only insufficiently express the natural CD28 ligands CD80 (=B7.1) and CD86 (=B7.2) at their cell surface. Thus the potentially tumor-specific T cells will obtain a single signal only for the interaction between the T cell receptor and MHC+tumor antigen and not the second costimulatory signal necessary for the full activation of a T cell. As a summary, this indicates that the immune system of B-CLL patients obviously is not capable of eliminating the tumor cells by itself.
One approach for therapy aims for improving the APC function of the B-CLL B cells and thus reinforcing the anti-tumor immune response of the patient. Various working groups have already tried to specifically activate B-CLL B cells and to thereby induce the expression of costimulatory ligands. They were successful in expressing, by gene transfer, the B cell stimulating CD40 ligand (CD40L) in the B-CLL B cells, and thus making possible the interaction between CD40L and the protein CD40 being present on all B cells (including the B-CLL B cells). The signal forwarded by CD40 into the cell interior led to the desired expression of the costimulatory ligand CD80 and CD86 (Kato et al., 1998; Wendtner et al., 2002). The leukemia cells thus modified could now in fact act in a more efficient way than APC's, and were now also eliminated—firstly in vitro—by autologous T cells (Kato et al., 1998). The in vivo gene transfer of CD40L was also effective: it led in the patients to an increase in the T cell count as well as to a reduction of the leukemic cells (Wierda et al., 2000). This therapeutic approach does not influence, however, the above mentioned T cell defects of the B-CLL disease.
In the following is shown the bibliography of the above scientific literature. Caligaris-Cappio, F., Rev Clin Exp Hematol 4, 5-21 (2000); Cantwell, M. et al., Nat Med 3, 984-989 (1997); Kato, K. et al., J Clin Invest 101, 1133-1141 (1998); Landis, S. H. et al., CA Cancer J Clin 49, 8-31 (1999); Rozman, C. et al., N Engl J Med 333, 1052-1057 (1995); Scrivener, S. et al., Leuk Lymphona 44, 383-389 (2003); Wendtner, C. M. et al., Blood 100, 1655-1661 (2002); Wierda, W. G. et al., Blood 96, 2917-2924 (2000).